Abnormal response to cortical activation in early stages of Huntington disease

Mochel, Fanny; Nguyen, Tra My; Deelchand, Dinesh K.; Rinaldi, Daisy; Valabrègue, Romain; Wary, C.; Carlier, Pierre; Dürr, Alexandra; Henry, Pierre Gilles

doi:10.1002/mds.25009

Cited by 45 publications

(62 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7 Recently, we have identified the inorganic phosphate (Pi)/phosphocreatine (PCr) ratio as an outcome measure of brain metabolic dysfunction in patients with HD. 8 We therefore aimed at obtaining a proof-of-concept of the effect of anaplerotic therapies on brain energy metabolism in HD using our 31 P functional MRS (fMRS) biomarker.…”

mentioning

confidence: 99%

“…The 31 P fMRS protocol has been previously described. 8 We targeted the visual cortex for the 31 P fMRS because it has higher energy metabolism, is easily stimulated, and is close to the scalp allowing an increased sensitivity to small surface coils. In addition, occipital volume loss has been reported in patients with HD.…”

mentioning

confidence: 99%

“…AMARES allows the inclusion of prior knowledge about relations between peaks and was used to obtain metabolite concentrations. 8 The ratio of Pi/PCr was calculated to determine the brain response to cortical activation.…”

mentioning

confidence: 99%

“…8 The Pi/PCr ratio has been linked to mitochondrial activation, and metabolic deficiency has been found to lead to an unusual change in Pi/ PCr in response to work. 12 The ratio is directly related to the ADP levels, which regulate mitochondrial oxidative metabolism.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Triheptanoin improves brain energy metabolism in patients with Huntington disease

et al. 2015

View full text Add to dashboard Cite

Objective: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proofof-concept of the therapeutic benefit of triheptanoin using a functional biomarker of brain energy metabolism validated in HD. Methods:We performed an open-label study using 31 P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed 31 P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with triheptanoin after which they returned for follow-up including 31 P brain MRS scan.Results: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controlsreflecting increased adenosine triphosphate synthesis-followed by a return to baseline levels during recovery (p 5 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation (p 5 0.005).Conclusion: This study suggests that triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. Huntington disease (HD) is characterized by autosomal dominant inheritance and motor, behavioral, and psychiatric symptoms. 1 There is strong evidence for hypometabolism in the brain of patients with HD. For example, glucose consumption is reduced, especially in the basal ganglia, even in presymptomatic mutation carriers.2-4 Studies in animal models have revealed decreased adenosine triphosphate (ATP) concentrations in the brain of HD mouse models. 5There are also nonneurologic symptoms at the early stage of the disease, such as weight loss despite enhanced caloric intake, which suggest a hypercatabolism in HD.6 Reduced concentrations of branched-chain amino acids (BCAAs)-valine, leucine, and isoleucine-have been found in plasma samples of patients with HD as early as in presymptomatic carriers even when they were on a high-caloric diet. 6 We hypothesized that decreased circulating levels of BCAAs reflect their mitochondrial oxidation in order to provide 2 key intermediates for the Krebs cycle: acetyl coenzyme A (acetyl-CoA) and succinyl-CoA. 6 Consequently, therapies aiming at From Inserm U 1127 (I.M.A., D.R., R

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Triheptanoin improves brain energy metabolism in patients with Huntington disease

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Another recent 31 P MRS study reported increased Pi/PCr and Pi/ATP ratios during visual stimulation in the occipital cortex (which reflects increased Pi and ADP levels to increase mitochondrial ATP production under normal aerobic conditions) in controls, but not in HD, suggesting an impairment in the adaptation to energy demand 117 . This abnormal response to activation was confirmed in a later study, which also demonstrated that treatment with triheptanoin, an anaplerotic compound Using 31 P MRS, it is also possible to perform magnetization transfer experiments to measure steadystate reaction rates for ATP synthase or creatine kinase (see 119 for review).…”

Section: P Nmr Spectroscopymentioning

confidence: 99%

Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases

Bonvento

Valette

Flament

et al. 2017

J Cereb Blood Flow Metab

Self Cite

View full text Add to dashboard Cite

show abstract

Energy Failure

Pathak

Berthet

Nakamura

2013

Annals of Neurology

134

View full text Add to dashboard Cite

Energy failure from mitochondrial dysfunction is proposed to be a central mechanism leading to neuronal death in a range of neurodegenerative diseases. However, energy failure has never been directly demonstrated in affected neurons in these diseases, nor has it been proved to produce degeneration in disease models. Therefore, despite considerable indirect evidence, it is not known whether energy failure truly occurs in susceptible neurons, and whether this failure is responsible for their death. This limited understanding results primarily from a lack of sensitivity and resolution of available tools and assays and the inherent limitations of in vitro model systems. Major advances in these methodologies and approaches should greatly enhance our understanding of the relationship between energy failure, neuronal dysfunction, and death, and help us to determine whether boosting bioenergetic function would be an effective therapeutic approach. Here we review the current evidence that energy failure occurs in and contributes to neurodegenerative disease, and consider new approaches that may allow us to better address this central issue.

show abstract

Abnormal response to cortical activation in early stages of Huntington disease

Abstract: (31)Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease.

Cited by 45 publications

References 16 publications

Triheptanoin improves brain energy metabolism in patients with Huntington disease

Triheptanoin improves brain energy metabolism in patients with Huntington disease

Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases

Energy Failure

Contact Info

Product

Resources

About